ABSTRACT The Natural Killer (NK) cell is a rapid effector arm of the innate immune response. Active before T cell responses, NK cells play a critical role against HIV and are regulated by a network of surface regulatory molecules, key among them the polymorphic KIR (killer Ig-like receptor). We propose to map the genetic variation of KIR - a potent and polymorphic regulator of NK cells ligated by HLA Class I alleles - to disease markers and NK cell function in a cohort of recently HIV-infected adults. Our research may determine if the NK response can be modulated to confer a novel mode of protection against HIV. Due to its complexity, only a fraction of KIR loci have been examined for disease or functional associations in HIV-1 infected persons. Studies on the role of KIR and HLA in HIV-1 disease have focused on the KIR3DS1/KIR3DL1 loci and its putative ligand, HLA Bw4Ile80 (a subset of Class I alleles), and have yielded contrasting results. Some studies have found evidence of an interaction conferring clinical protection, while others have observed no evidence for an interaction. Other KIR genes are largely unexplored in HIV disease. Hence, we have intriguing but incomplete information about the role of KIR and NK function in HIV. To chart this complex system, we will employ a novel mass spectrometry-based DNA sequencing method to chart the entire KIR gene cluster and the HLA Class I A, B, and C loci to NK cell functional profile (NK IFN-g, CD107a in a 721.221 target cell system) and early disease markers in a large, longitudinal study of 1500 adults from a North American and Brazilian early HIV infection cohort. We aim (1) To describe the KIR gene cluster, and the HLA A, B and C loci in 1300 recently infected adults; (2) To chart KIR and HLA genetics to NK effector function in these 1300 adults and (3) To perform KIR/HLA genetics and NK functional assays in a group of 200 HIV-1 exposed uninfected adults. The HIV-exposed uninfected group will allow assessment of the role of KIR/HLA in protection against HIV-1 acquisition and effects of HIV-1 infection on NK function. Our Brazil cohort enables us to further examine KIR and HLA effects on untreated subtype B infection, as treatment is not initiated until a CD4+ count of 300 cells/ul.